The alarming worldwide increase in obesity - together with a surge in associated insulin resistance (IR) and type 2 diabetes (T2D) - follows marked changes in diet and physical activity over the past generation. However relationships between diet, obesity, and IR are complex. It is now evident that obesity and IR are strongly associated with a chronic inflammatory state, which in turn perpetuates metabolic dysregulation, in a self-amplifying loop. We and others recently identified an unexpected role for the immune receptor CD40, expressed by CD8 T cells, in regulating inflammation of visceral adipose tissue (VAT), obesity, and IR. There is thus is a critical need to understand this newly recognized regulatory role for CD40. Our long-term goal is to define the biological role of CD40 expressed by CD8 T cells in chronic inflammation. The objective of the proposed project is to determine how CD40 regulates CD8 T cell function in the pathogenesis of VAT inflammation and IR. Our working hypothesis is that CD8 T cells are recruited to the VAT by adipokines and cytokines, where they in turn recruit and activate inflammatory macrophages. In this inflammatory environment, CD40 is upregulated on CD8 T cells, which restrains the development of VAT inflammation and metabolic dysregulation, by limiting T cell activation, and hence further macrophage activation. We will test this hypothesis via the following experimental Aims: 1) How do cell-cell interactions and T cell activation status in the VAT mediate the regulatory role of CD40 in obesity and IR? 2) How does CD40 regulate the functions of CD8 T cells in the VAT, to protect against inflammation, obesity and IR? The expected outcome of these studies to determine the mechanisms by which CD40 mediates protection from chronic VAT inflammation that exacerbates obesity and development of IR, knowledge that will serve as an important basis for translational studies in human adipose tissue, and development of new approaches to combat obesity-induced IR and type 2 diabetes.